Math Casts New Light on Long-Studied Biological Process

For years biologists have taught their students that the process bacteria use to quickly adapt to metabolize preferred energy sources such as glucose is controlled only by glucose. Now, with some help from mathematics, researchers have demonstrated that the process, known as “catabolite repression,” is controlled not just by glucose, but also by other essential nutrients in a growth medium, such as nitrogen and sulfur.

The study is published in this week’s advance online publication of Nature.

Terence Hwa, Ph.D., a professor of physics and biology at the University of California, San Diego, and his team arrived at their surprising finding by employing a new approach called “quantitative biology,” in which scientists quantify biological data and discover mathematical patterns, which in turn guide them to develop predictive models of the underlying processes. Colleagues from Peking University in China, the University of Marburg in Germany, and the Indiana University School of Medicine collaborated on the study.

“Molecular biology gives us a collection of parts and interactions,” said Dr. Hwa. “But how do you make sense of those interactions? You need to examine them in their physiological context. Quantitative patterns in physiological responses, together with mathematical analysis, provide important clues that can reveal the functions of molecular components and interactions, and in this case, also pinpoint the existence of previously unknown interactions.”

Biologists have long known that when glucose is the primary carbon source for cells, bacteria such as E. coli repress genes that allow the organism to metabolize other kinds of sugars. This catabolite repression effect is controlled by cyclic adenosine monophosphate (cAMP).

“Previously, it was thought that glucose uptake sets the cAMP level in the cell,” continued Dr. Hwa. “But we discovered that in reality, it’s the difference between carbon uptake and the uptake of other essential nutrients such as nitrogen. So the picture now is very different.”

The UC San Diego scientists unraveled this relationship by measuring the level of cAMP and the level of enzymes that break down sugar molecules in bacterial cells against the growth rates of the bacteria, while subjecting these cells to limiting supplies of carbon, nitrogen, and other compounds.

“When we plotted our results, our jaws dropped,” said Dr. Hwa. “The levels of the sugar uptake and utilization enzymes lined up remarkably into two crossing lines when plotted with the corresponding growth rates, with the enzyme level increasing upon carbon limitation and decreasing upon nitrogen and sulfur limitation. The enzyme levels followed the simple mathematical rules like a machine.”

From the overall pattern, it is clear that there’s nothing special about glucose, he pointed out. “Now we know this process is not about the preference of glucose over other carbon compounds, but rather the fine coordination of carbon uptake in the cell with other minor, but essential nutrient elements, such as nitrogen and sulfur.”

Dr. Hwa believes that the results of the study may be valuable to the fermentation industry, where metabolic engineers strive to rewire the genetic programs of industrial microorganisms to increase their yield of desirable products, such as insulin for biomedical applications and ethanol for bioenergy. Other applications for this new knowledge include the study of obesity as well as cancer, he added.